Endometrial carinoma is the most common cancer of the female reproductive tract. Most endometrial cancers are found at an early stage and present with postmenopausal bleeding. These patients are initially treated with comprehensive surgical staging. This treatment is often diagnostic ofthe extent of disease and therapeutic. However, a key clinical problem in the management of patients with uterine cancers is how to best fre[unreadable]t~ab\r[unreadable]rhced'stagieclisease ahdlhe aggressive pathoTogic histotypes that account for signficant mortality. Patients with high stage or recurrent cancers have systemic disease requiring novel therapeutic interventions. Effective therapies are largely lacking. A better understanding ofthe cancer biology, such as signal transduction pathways, will lead to new treatment strategies that will improve the survival of these patients. Activation of the Mitogen Activating Pathway Kinase signaling pathway contributes substantially to endometrial tumorigenesis. Our group has identified thirty novel ERK substrates through a three-part functional genomic approach in the C. elegans model. The human orthologs of these proteins expressed in endometrial cancer cell lines are candidate ERK substrates. Thus far, of the candidates studied, we showed that GSK3n is important to cell growth in multiple endometrial cancer cell lines and has potential for therapeutic interventions.. In this proposal, we will continue to characterize novel ERK candidate substrates in endometrial cancer. In Aim 1, we will assess expression of candidate ERK1/2 substrates in the normal endometrium, primary endometrial cancers and endometrial cancer cell lines and determine if substrate phosphorylation is ERK-dependent. Then in aim 2, we will determine the relationship between ERK substrate phosphorylation status and upstream ERK signaling pathway activation in primary endometrial cancers and clinicopathologic significance of ERK substrate expression. Finally in aim 3, we will explore GSKSD inhibition as potential therapy for endometrial cancer and assess the role of inhibiting other ERK substrates plays in endometrial cancer cell lines. Together these studies should provide a better understanding of the role the ERK pathway plays in endometrial carcinogenesis and may lead to improved clinical biological therapies. RELEVANCE (See instructions): The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.